Safety and pharmacokinetics of BI 685509, a soluble guanylyl cyclase activator, in patients with cirrhosis: A randomized Phase Ib study

Background: Portal hypertension is a severe complication of cirrhosis. This Phase Ib study (NCT03842761) assessed the safety, tolerability, and pharmacokinetics of soluble guanylyl cyclase activator BI 685509 in patients with mild or moderate hepatic impairment (Child–Pugh [CP] A or B cirrhosis) and healthy volunteers (HVs). Methods: In this single-center, randomized, placebo-controlled study, patients received BI 685509 (maximum doses: 1, 2, or 3 mg, twice daily [BID]) or placebo for 28 days. HVs received one 0.5 mg dose of BI 685509 or placebo. Results: In total, 64 participants (CP-A, n=24; CP-B, n=25; HVs, n=15) were included; most commonly with NAFLD (36.7%), alcohol-associated (30.6%), or chronic viral hepatitis-related cirrhosis (28.6%). In patients with CP-A cirrhosis, drug-related adverse events (AEs) occurred in 5.6% of BI 685509-treated patients and 16.7% of placebo recipients. In patients with CP-B cirrhosis, drug-related AEs occurred in 26.3% of BI 685509-treated patients only. No serious AEs occurred in patients with CP-A cirrhosis; in patients with CP-B cirrhosis, serious AEs (not drug-related) occurred in 10.5% of BI 685509-treated patients and 16.7% of patients receiving placebo. BI 685509 was rapidly absorbed; exposure increased with dosage and was similar between etiologies and between patients with CP-A cirrhosis and patients with CP-A cirrhosis but lower in HVs. The mean percentage portal–systemic shunt fraction was measured in patients with CP-A cirrhosis and decreased at the end of treatment in the 2 mg BID (–11.2 ± 11.9%) and 3 mg BID (–14.0 ± 8.4%) BI 685509 dose groups, but not in the placebo group (+1.0 ± 27.3%). Conclusion: BI 685509 was generally well tolerated, with 3 serious, not drug-related AEs reported in patients with CP-B cirrhosis. In patients with CP-A cirrhosis, portal–systemic shunt fraction in the exploratory efficacy analysis was reduced by 2 mg BID and 3 mg BID BI 685509.


INTRODUCTION
Cirrhosis is a devastating outcome of chronic inflammation in the liver, with over 122 million cases of cirrhosis resulting in 1.32 million deaths worldwide. [1][5] While there are no treatments that specifically target PH, [2,6] off-label nonselective betablockers (NSBBs) to reduce portal venous inflow [7] and endoscopic variceal ligation to prevent bleeding are commonly used.However, many studies suggest that there is a narrow "therapeutic window" for the use of NSBBs between the development of esophageal varices and the complications of advanced cirrhosis. [8]Moreover, considering that ligation does not influence the fundamental issue of PH [2,6] and may potentially trigger severe ulcer bleeding associated with the procedure, [9] this approach must be employed with caution and limited to select patients.Therefore, there remains a large unmet need for effective therapies that directly target PH.
Disrupted nitric oxide (NO) synthesis is a hallmark of PH pathophysiology. [10]The primary receptor for NO is soluble guanylyl cyclase (sGC), which, upon activation by NO, catalyzes the formation of cyclic guanosine monophosphate from guanosine triphosphate, [11,12] promoting vasodilation and smooth-muscle relaxation. [13]Studies show that both NO and cyclic guanosine monophosphate production decrease in models of cirrhosis, leading to HSC activation. [14,15]Activated HSCs constrict hepatic sinusoids by adopting contractile characteristics causing restricted portal flow, promoting venous congestion.18] Recently developed sGC modulators exhibit diverse effects across cardiac, renal, and liver diseases, including reduction of fibrosis and portal pressure, [13,19] impacting both dynamic (vasoactive) and static (fibrosis) PH components. [20,21]Further studies have shown that sGC activators bind to the heme-binding domain, mimicking NO-bound heme and activating the NO-unresponsive form of sGC. [22]This suggests that sGC activators have greater pharmacological activity than sGC stimulators, such as BAY 41-2272, under pathophysiological conditions and oxidative stress. [23]herefore, sGC activators represent a potential therapeutic avenue for conditions such as clinically significant PH (HVPG ≥ 10 mm Hg [24] ).
BI 685509 is an NO-independent sGC activator currently being investigated in patients with PH to slow cirrhosis progression and reduce portal pressure.This Phase Ib clinical trial examined the safety, tolerability, and pharmacokinetics (PK) of BI 685509 in patients with mild (Child-Pugh [CP]-A) or moderate (CP-B) hepatic impairment, using different dosing schemes and compared single doses of BI 685509 in patients and individually matched healthy volunteers (HVs).

Study design and participants
This single-center, randomized, placebo-controlled, double-blind (within dose groups), parallel-group, dose-escalation, Phase Ib study investigated 3 dosing schemes of BI 685509 in patients with mild or moderate hepatic impairment and compared single BI 685509 doses in patients with matched HVs.The planned enrolment was 64 participants: 48 patients with hepatic impairment (24 each per CP-A/CP-B), and 16 HVs.
All eligible participants were aged ≥ 18 years, with a MAP of ≥ 85 mm Hg and an estimated glomerular filtration rate of > 70 mL/min/1.73m 2 at screening.Patients with hepatic impairment were classified into 2 groups by CP score (CP-A5/A6 for compensated cirrhosis and CP-B7/ B8/B9 for decompensated cirrhosis), and all patients had liver stiffness > 15 kPa.Patients with CP-A cirrhosis did not show any clinical evidence of decompensation; however, previous decompensation events that were self-limited and resolved were allowed if they had occurred ≥ 6 weeks before screening and did not require continued therapeutic intervention at screening.HVs were included if they were deemed healthy by the investigator's assessment, and they were individually matched to a patient with CP-A or CP-B (age ± 5 y, bodyweight ± 15%, sex).
Participants were excluded if they had ongoing chronic alcohol or drug use (which, in the investigator's opinion, would have resulted in unreliable results or the inability to complete the trial), history of relevant orthostatic hypotension, major operation within 12 weeks prior to screening, primary sclerosing cholangitis, primary biliary cholangitis or HIV, or if they were pregnant or nursing.Patients with CP-B cirrhosis were excluded if they had refractory ascites or a recent decompensation event within 6 weeks of screening.
All patients provided written informed consent before study enrollment, and these studies were conducted in accordance with Good Clinical Practice (CPMP/International Council on Harmonisation/135/95), ethical principles laid down in the 2013 Declaration of Helsinki, and applicable regulatory requirements.

Randomization and blinding
Participants within each patient group (CP-A/-B) were randomized 3:1 to receive oral tablets of BI 685509 (1 of 3 dose groups; maximum tested doses after dose escalation: 1 mg twice daily [BID], 2 mg BID, 3 mg BID) or placebo (Supplemental Table S1, http://links.lww.com/HC9/A535).A randomization list with study medication numbers, developed by the sponsor, was provided to the trial site.This randomization list was generated using a validated system involving a pseudorandom number generator.All trial participants, investigators, and site staff were blinded to the assigned treatment.Dose escalation was carried out sequentially, with a dose group receiving treatment only after the previous group had completed treatment and safety had been confirmed.HVs received a single dose of the same treatment as the individually matched patient (0.5 mg BI 685509 or placebo).Administered treatments were blinded within dose groups.

Procedures
Treatment was administered to patients on site after an overnight fast on days 1, 4-5, 10-11, 16-17, and 27-28.Treatment administered at home (days 6-9, 12-15, and 17-26) was taken with a glass of water immediately before or during breakfast (and dinner if BID) at approximately the same time each day; for BID dosing, there was an interval of ≥ 10 hours between doses.On days 5, 11, and 17, the morning dose was administered on site, and the second dose was administered at home.Treatment was administered to HVs on site after an overnight fast on day 1.PK were assessed on days 1-4; vital signs were assessed on days 1, 2, and 4; 12-lead ECG, physical examinations, and orthostatic tests were assessed on days 1 and 4; and AEs were assessed daily from screening to the end of observation (day 8).

End points
The primary end point was the number of patients with drug-related AEs across different dose regimens over each dose escalation.Secondary safety end points were assessed after 28 days of treatment as the change from baseline in seated systolic BP, seated diastolic BP, HR, and bodyweight.Further safety end points were assessed based on treatment-emergent adverse events (TEAEs), safety laboratory parameters, vital signs, and 12-lead ECG.
Secondary PK end points were AUC from time 0 to the last quantifiable data point (AUC 0-tz ) and the observed C max of BI 685509 after the first drug administration up to 72 hours in patients and HVs, and the AUC at steady state over a uniform dosing interval τ (AUC τ,ss ) and C max at steady state (C max,ss ) of BI 685509 after the last drug administration up to 72 hours in patients with CP-A/B cirrhosis.
Exploratory efficacy end points in patients with CP-A and CP-B cirrhosis were the change from baseline in liver stiffness measured by FibroScan (any available model; Echosens) on days 16 and 27, and in patients with CP-A cirrhosis only, the change from baseline in spleen stiffness measured by FibroScan (Expert 630 Professional; Echosens) on days 16, 17, 27, and 28, and the change from baseline in liver function measured by the disease severity index, d4-cholate at 60 minutes (HepQuant STAT), and SHUNT using the HepQuant SHUNT test (HepQuant) on days 11 and 27.Additional exploratory end points included total serum levels of cytokeratin 18 (M65), caspasecleaved cytokeratin 18 (M30), Pro-C3, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyltransferase, bilirubin and C-reactive protein, and composite scores (enhanced liver fibrosis test, NAFLD fibrosis, fibrosis-4, aspartate aminotransferase-to-platelet ratio index, and MELD.The changes from baseline after 27 days of treatment in patient-reported outcomes (EQ-5D-5L and chronic liver disease questionnaires) were defined as other end points.

Statistical analyses
The planned sample size for this trial was not based on a power calculation.This study planned to include 64 participants: 16 HVs and 48 patients (8 patients per patient group [CP-A/-B] and dose group: 6 on active treatment, 2 on placebo; this is common in multiple rising dose studies of this type and is considered sufficient to detect major differences between dose groups and placebo in terms of the primary end point).A sample size of 6 per group (patients with hepatic impairment and HVs) is considered sufficient for hepatic impairment trials.
Safety, tolerability, PK, and exploratory end points were assessed using descriptive statistics.The effect of hepatic impairment on the PK of BI 685509 was assessed using an ANOVA model, and differences between BI 685509 treatment and placebo for systolic BP, diastolic BP, and MAP were assessed at day 28 using a linear regression model.PK parameters were calculated by noncompartmental analysis using Phoenix WinNonlin software (version 8.1; Pharsight Corporation, Mountain View, CA, USA).

Trial registration
The trial was registered with ClinicalTrials.gov(NCT03842761).

Study participants and compliance
In total, 96 participants were screened (CP-A, n = 41; CP-B, n = 35; HVs, n = 20; March 8, 2019, to February 3, 2021); of these, 24 patients with CP-A cirrhosis (n = 6 each per dose group and placebo), 25 patients with CP-B cirrhosis (n = 6 each per 1 mg BID and 2 mg BID; n = 7, 3 mg BID; n = 6, placebo), and 15 HVs (n = 12, BI 685509 0.5 mg once daily; n = 3, placebo) were treated (Figure 1).Participant characteristics and demographics were similar between dose groups and CP groups and between matched HVs and patients with CP-A and CP-B cirrhosis in the 1 mg BID dose group (Table 1).However, almost two-thirds of patients with CP-B cirrhosis were male, and the proportion of male patients varied between dose groups.Cirrhosis history (cause of cirrhosis, prior decompensation events) varied between patients with CP-A and CP-B cirrhosis: 7 patients with CP-A cirrhosis (29.2%) and 24 patients with CP-B cirrhosis (96.0%) had a prior decompensating event.The CP-B patient with no prior decompensation event was included in this arm because of high bilirubin levels at baseline ( > 3 mg/dL).
During the trial, 1 patient with CP-A cirrhosis (4.2%, placebo) and 3 patients with CP-B cirrhosis (12.0%; n = 1 each per 2 mg BID, 3 mg BID, and placebo) discontinued trial medication: 2 due to an AE (CP-B, n = 1 each per 3 mg BID [delirium] and placebo [hematemesis, non-variceal]) and 2 due to withdrawal by participant (CP-A: n = 1, placebo; CP-B: n = 1, 3 mg BID).All treated patients with CP-A and CP-B cirrhosis and matched HVs were included in the biomarker set and the ECG plasma concentration set, and all patients with CP-A and CP-B cirrhosis and HVs on active treatment were included in the PK parameter analysis.

Safety
Investigator-defined, drug-related AEs (primary end point) were reported for 2 patients with CP-A cirrhosis (8.3%: n = 1, 3 mg BID; n = 1, placebo) and 5 patients with CP-B cirrhosis (20.0%: n = 3, 2 mg BID; n = 2, 3 mg BID) (Table 2).Five patients were reported with orthostatic intolerance (n = 1, CP-A 3 mg BID; n = 2 each per CP-B 2 mg BID and CP-B 3 mg BID), 1 patients with CP-A cirrhosis receiving placebo was reported with dizziness, and 1 patients with CP-B cirrhosis in the 2 mg BID dose group was reported with diarrhea.
TEAEs were reported for 3 patients with CP-A cirrhosis (12.5%) and 8 patients with CP-B cirrhosis (32.0%); no HVs reported TEAEs (Table 2).The most frequent TEAEs in patients with CP-A cirrhosis were orthostatic intolerance (n = 1, 3 mg BID), dizziness (n = 1, placebo), and influenza-like illness (n = 1, 1 mg BID).The most frequent TEAE in patients with CP-B cirrhosis was orthostatic intolerance (n = 4: n = 2 each per 2 mg BID and 3 mg BID).No serious AEs or AEs leading to discontinuation of the trial drug were reported in patients with CP-A cirrhosis.Three serious AEs were reported in patients with CP-B cirrhosis (n = 1 each per ascites, 1 mg BID; delirium, 2 mg BID; hematemesis [non-variceal], placebo), 2 of which led to discontinuation of the trial drug, but none of these AEs were considered drugrelated.
No relevant changes from baseline in systolic BP, diastolic BP, HR, bodyweight (secondary end points), MAP, hip circumference, or waist circumference were seen in patients with CP-A or CP-B cirrhosis at day 28 or in HVs (Table 3).At day 28, no significant difference was seen between patients treated with BI 685509 and patients who received a placebo for systolic BP, diastolic BP, or MAP (p > 0.05).However, over the course of the study, decreases from baseline in 1 hour postdose systolic BP and 1 hour postdose diastolic BP were seen in patients treated with BI 685509 compared with placebo, although no clear dose relationship was seen in either patients with CP-A or CP-B cirrhosis (Supplemental Figures S1A-D, http://links.lww.com/HC9/A535).Overall, HR increased from baseline at 1 hour postdose in patients with CP-A cirrhosis receiving 3 mg BID BI 685509 and patients with CP-B cirrhosis receiving 2 mg and 3 mg BID BI 685509 (Supplemental Figures S1E and F, http://links.lww.com/HC9/A535).Overall, 5 patients were reported with orthostatic dysregulation (n = 1, CP-A 3 mg BID; n = 2 each per CP-B 2 mg BID and 3 mg BID); no matched HVs were reported with orthostatic dysregulation.For CP-A 1 mg BID and CP-B 2 mg BID patients, systolic BP after standing up tended to decrease for all 1 hour postdose measurements compared with predose measurements, and pulse rate tended to increase 1 hour postdose compared with predose measurements (Supplemental Figure S2, http://links.lww.com/HC9/A535).Notable ECG findings were reported for HR in 2 patients with CP-A cirrhosis (2 mg BID, 45.2-51.1% decrease; 3 mg BID, 46.1% increase), and an increased QT interval ( > 500 msec) was reported for 1 CP-B patient on day 1 of treatment (1 mg BID; QT interval 502 msec).No clinically relevant findings were reported for HVs.A new onset of maximum QT interval corrected by Frederica's formula (QTcF) interval (QTcF interval > 500 msec or change from baseline of > 60 msec at any time of treatment) was observed in 7 patients with CP-A cirrhosis (n = 1, 1 mg BID; n = 3, 2 mg BID; n = 2, 3 mg BID; and n = 1, placebo) and 9 patients with CP-B cirrhosis (n = 3, 1 mg BID; n = 5, 2 mg BID; and n = 1, 3 mg BID).In addition, only BI 685509-treated patients had an increase from baseline in QTcF of ≥ 30 msec or QT of ≥ 60 msec, although no dose relationship was observed.The time profiles of QTcF and HR changes from baseline were similar between patients with CP-A and CP-B cirrhosis; no notable findings were observed in patients receiving placebo.
Two patients with CP-A cirrhosis progressed to CP-B during treatment (n = 1 each per 1 mg BID and 3 mg BID), with the patient in the 3 mg BID dose group returning to CP-A at follow-up.Two patients with CP-B cirrhosis were reported with a temporary shift to CP-A (n = 1 each per 1 mg BID and placebo), and 1 patient reported a temporary shift to CP-C (1 mg BID) due to decreased serum albumin.All patients reporting a shift in CP classification continued treatment.
During treatment, 7 patients with CP-A cirrhosis and 12 patients with CP-B cirrhosis (no HVs) had slightly raised direct bilirubin levels (maximum values: 0.43-0.76mg/dL and 0.44-1.24mg/dL, respectively).Of these, only 2 episodes were considered possibly clinically significant (both in patients with CP-B cirrhosis; maximum values: 1.14 mg/dL and 1.24 mg/dL).Furthermore, during treatment, 12 patients with CP-A cirrhosis, 11 patients with CP-B cirrhosis, and 1 HV had slightly raised alkaline phosphatase levels (maximum values: 119-214 U/L, 118-203 U/L, and 151 U/L, respectively); none of these episodes were considered clinically significant.

PK outcomes
Following single and multiple oral administrations of BI 685509 in patients with mild or moderate hepatic impairment, the drug was rapidly absorbed (median t max(ss) , 0.5-2.0hours) and exposure (C max(ss) and AUC (ss) ) of BI 685509 increased with dose (Table 4).Plasma concentration-time profiles were similar after single-dose administration on day 1 between patients with CP-A cirrhosis, patients with CP-B cirrhosis, and matched HVs (Figure 2A) and after multiple doses on days 28-31 between patients with CP-A and CP-B cirrhosis; however, concentrations of BI 685509 were higher in patients with CP-A and CP-B cirrhosis compared with matched HVs.
The PK of multiple doses of BI 685509 were consistent with the single-dose results and between patient groups (Table 4).The apparent clearance (CL/F and CL/F ss ), volume of distribution (V z and V z /F ss ), terminal elimination half-life (t 1/2 and t 1/2,ss ), and renal clearance were comparable between patients with CP-A and CP-B cirrhosis (Table 4).Overall, estimates of AUC 0-tz and C max and the geometric means of AUC τ,ss and C max,ss were similar between patients with CP-A and CP-B cirrhosis (Figure 2B and C; Table 4); both parameters at steady state were slightly lower for CP-B 3 mg BID, and AUC τ,ss was slightly higher for CP-B 1 mg BID, compared with patients with CP-A cirrhosis.Dosenormalized C max,ss and AUC τ,ss values were similar between the different cirrhosis etiologies on day 28 (Figure 2D and E).
A comparison of patients with hepatic impairment with matched HVs showed that exposure was ~40% and ~27% higher in patients with CP-A and CP-B cirrhosis, respectively.The CL/F and V Z /F were lower in patients compared with matched HVs, whereas the fraction of dose excreted (fe 0-24 ) and renal clearance from 0 to 24 hours (CL R,0-24 ) were higher in patients.The t 1/2 was comparable between patients and their matched HVs.

Efficacy outcomes
The change from baseline in spleen stiffness was inconclusive due to a high proportion of invalid measurements (31%) and technical and biological variability (Supplemental Table S2, http://links.lww.com/HC9/A535).Although no significant changes in median spleen stiffness occurred over time, the available paired endof-treatment/baseline spleen stiffness ratios were all ≤ 1 for all patients with CP-A cirrhosis (Figure 3).
At baseline, liver stiffness was higher in patients with CP-B cirrhosis (median 28.8-46.7 kPa) compared with patients with CP-A cirrhosis (median 23.0-29.3kPa; Table 1), and no treatment effect was seen for liver stiffness, fat content, or Pro-C3 levels (Supplemental Table S2, http://links.lww.com/HC9/A535);large interindividual variability was seen for liver stiffness values.
Overall, no relevant differences between patient groups or treatment groups or relevant changes from baseline were observed for any assessed biomarkers, composite scores, or patient-reported outcomes (Supplemental Table S2, http://links.lww.com/HC9/A535).

Safety
In this Phase Ib trial, BI 685509 was generally well tolerated, with 2 AEs leading to treatment discontinuation and 3 serious AEs, restricted to patients with CP-B cirrhosis and assessed as not drug-related.The frequency of TEAEs and drug-related AEs was higher in patients with CP-B cirrhosis (32.0% and 20.0%, respectively) compared with patients with CP-A cirrhosis (12.5% and 8.3%, respectively), with orthostatic intolerance being the most frequently reported drugrelated AE (n = 1 each per CP-A 3 mg BID, CP-B 2 mg BID, and CP-B 3 mg BID).Decreases in systolic and diastolic BP and an increase in HR were seen in patients receiving BI 685509 compared with placebo; however, no dose relationship was observed in either patient group.This could be a benefit of the mechanism of action of this therapy compared with NSBBs, with which hypotension often occurs in patients with CP-B cirrhosis. [25]However, drug-related orthostatic dysregulation occurred in 5 patients receiving BI 685509 (n = 1, CP-A 3 mg BID; n = 2 each per CP-B 2 mg BID and 3 mg BID).Although no relevant effects of BI 685509 on vital signs were identified during orthostatic testing, trends of decreased standing systolic BP and increased pulse rate were observed in CP-A 1 mg BID and CP-B 2 mg BID patients.Additionally, increases in HR and in QTcF and QT intervals were observed.However, only a limited number of data points were available in the concentration-QTcF analysis, such that the results may be interpreted with caution.Overall, no relevant cardiac arrhythmias occurred, and the clinical relevance of QT interval changes is currently unknown.Nonetheless, these changes led to the identification of a potential risk of QT prolongation following BI 685509 treatment, the implementation of risk minimization strategies, and the inclusion of regular QT assessments in subsequent clinical studies.

PK outcomes
As BI 685509 is expected to be primarily eliminated by the liver (unpublished data), it is anticipated that hepatic impairment may lower the overall clearance of BI 685509, leading to higher systemic exposure.Indeed, when compared with matched HVs, apparent clearance was ~27% and ~19% lower in CP-A and CP-B patients, respectively.In addition, BI 685509 total exposure in patients with hepatic impairment (AUC 0-tz ) was ~30-40% higher compared with matched HVs.Although exposure was higher in patients with hepatic impairment T A B L E 2 Summary of treatment-emergent adverse events according to cirrhosis Child-Pugh class and BI 685509 dose T A B L E 3 Change from baseline in secondary safety end points at day 28 Change from baseline at day Waist circumference, cm 0.

Efficacy outcomes
In this study, treatment with the 2 highest doses of BI 685509 dose-dependently decreased mean portalsystemic shunt fraction.The HepQuant SHUNT test uses the hepatic uptake of cholate from the systemic and portal circulations to assess liver function and portal blood flow. [26]Progressive liver disease is associated with a decrease in cholate clearance and an increase in portal-systemic shunting, thereby allowing the test to identify the risk of complications in patients with compensated cirrhosis. [26]This test is also capable of the early, noninvasive detection of PH, with a reliability similar to that of HVPG. [27]However, while HVPG remains the gold standard method for assessing PH, and its use is encouraged in clinical trials, it is invasive and requires considerable resources and expertise. [28]herefore, HepQuant SHUNT and other noninvasive biomarkers (eg, spleen stiffness measurements [28] ) may complement HVPG in the short term and perhaps replace it in the future.Although spleen stiffness may identify a portal pressure decrease in response to NSBBs, [29] the current study was the first clinical trial to use spleen stiffness as assessed by a dedicated vibration-controlled transient elastography device (ie, FibroScan Expert 630 Professional) as a surrogate end point for PH.However, spleen stiffness measurements in the present study showed high intraindividual variability and were invalid and inconclusive in many patients.There are several reasons why the results had a high degree of variability.First, spleen stiffness measurements can have lower repeatability than liver stiffness measurements. [30]While the device used for this study (FibroScan 630 Expert) uses a novel 100 Hz probe specifically designed for spleen stiffness measurements, [31] the measurement depth of the probe (M-Probe) is limited to between 25 and 65 mm.Notably, since the mean body mass index was > 30 kg/m 2 (the definition of obesity) for each patient group and for HVs in this study, there tended to be a long skin-to-spleen distance.This increased distance may make the probe nonoptimal for use in people with obesity. [32]Finally, spleen stiffness measurements can depend on operator experience.The disruption caused by the COVID-19 pandemic made training for this novel device difficult, possibly resulting in less-experienced investigators and, therefore, more variable measurements.Further exploration of spleen stiffness as a noninvasive biomarker for PH in future clinical trials is warranted, including the optimization of probe use for patients with a high body mass index.

Limitations
A limitation of this study was the short treatment duration, with only 12 days spent on the dose-escalated maintenance dose.This may explain why biomarkers of liver function and liver stiffness measurements remained unchanged; however, the primary end point of this study was to assess the safety and tolerability of BI 685509 and not to explore efficacy end points.In addition, the low number of included patients could have influenced the power of the exploratory outcomes.Furthermore, although most patients with CP-A cirrhosis did not show any clinical evidence of decompensation, some patients may have experienced self-limiting and resolved decompensation events ≥ 6 weeks before screening.During the study, some patients with CP-A cirrhosis may have had disease characteristics similar to patients with CP-B cirrhosis; however, only 2 patients with CP-A cirrhosis progressed to clinically evident CP-B during treatment.In addition, phosphatidylethanol blood alcohol testing was not conducted to confirm alcohol abstinence throughout the trial.However, participants were excluded if they had ongoing chronic alcohol or drug use.
,34] Phase II studies of BI 685509 in patients with cirrhosis have been designed and are ongoing to investigate the efficacy of BI 685509 to ameliorate PH (ie, to decrease HVPG).

CONCLUSIONS
This Phase Ib clinical trial examined the safety, tolerability, and PK of BI 685509, an sGC activator, in patients with CP-A or CP-B cirrhosis and HVs.This study demonstrated that multiple rising doses of BI 685509 were generally well tolerated in patients with mild or moderate hepatic impairment, with 3 serious AEs reported (all in patients with CP-B cirrhosis) and none considered to be drug-related.The PK and exposure of BI 685509 were similar between patient groups with mild (ie, CP-A) versus moderate (ie, CP-B) hepatic impairment and across different cirrhosis etiologies.Exposure of BI 685509 in matched HVs was lower compared with patients with hepatic impairment.While paired spleen stiffness measurements all decreased with BI 685509 treatment, the high failure rate of the technique, likely due to the prevalence of obesity in this population, limits this conclusion.The HepQuant SHUNT test results suggest that high doses of BI 685509 reduce portal-systemic shunting, indicating improved hepatic function.Thus, this trial supports further evaluation of BI 685509 for the treatment of patients with cirrhosis and PH.

DATA SHARING STATEMENT
To ensure independent interpretation of clinical study results and enable authors to fulfill their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data.In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript and secondary analyses in peer-reviewed journals and regulatory and reimbursement activities are completed, normally within 1 year after the marketing application has been granted by major Regulatory Authorities.Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharingfor further information.

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I G U R E 1 Participant disposition.(A) Child-Pugh class A and B patients; (B) healthy volunteers.*One CP-B patient in the 2 mg BID group was removed from the trial due to a serious AE of delirium.Abbreviations: AE, adverse event; BID, twice daily; CP, Child-Pugh.T A B L E 1 Patient demographics, disease characteristics, and biomarkers CP-A cirrhosis CP-

F I G U R E 3
Spleen stiffness in patients with Child -Pugh class A cirrhosis.Data are presented as mean ± SD, with individual values represented.Abbreviations: BID, twice daily; EoT, end of treatment.F I G U R E 4 Change in portal-systemic shunt fraction in patients with Child-Pugh class A cirrhosis as measured by the HepQuant SHUNT test.Data are presented as mean ± SD.Abbreviations: BID, twice daily.
BID, twice daily; CL/F, apparent clearance; CL R , renal clearance; CP, Child-Pugh; fe, fraction of dose excreted; gCV, geometric coefficient of variation; gMean, geometric mean; MRT, mean residence time; PK, pharmacokinetic; PTF, peak-trough fluctuation; t max , time to peak plasma concentration; V Z /F, apparent volume of distribution. a